Reproducibility of quantitative 18F-3′-deoxy-3′-fluorothymidine measurements using positron emission tomography
Positron emission tomography (PET) using 18F-3′-deoxy-3′-fluorothymidine ([18F]FLT) allows noninvasive monitoring of tumour proliferation. For serial imaging in individual patients, good reproducibility is essential. The purpose of the present study was to evaluate the reproducibility of quantitative [18F]FLT measurements.
Nine patients with non-small-cell lung cancer (NSCLC) and six with head-and-neck cancer (HNC) underwent [18F]FLT PET twice within 7 days prior to therapy. The maximum pixel value (SUVmax) and a threshold defined volume (SUV41%) were defined for all delineated lesions. The plasma to tumour transfer constant (Ki) was estimated using both Patlak graphical analysis and nonlinear regression (NLR). NLR was also used to estimate k3, which, at least in theory, selectively reflects thymidine kinase 1 activity. The level of agreement between test and retest values was assessed using the intraclass correlation coefficient (ICC) and Bland-Altman analysis.
All primary tumours and >90% of clinically suspected locoregional metastases could be delineated. In total, 24 lesions were defined. NLR-derived Ki, Patlak-derived Ki, SUV41% and SUVmax showed excellent reproducibility with ICCs of 0.92, 0.95, 0.98 and 0.93, and SDs of 16%, 12%, 7% and 11%, respectively. Reproducibility was poor for k3 with an ICC of 0.43 and SD of 38%.
Quantitative [18F]FLT measurements are reproducible in both NSCLC and HNC patients. When monitoring response in individual patients, changes of more than 15% in SUV41%, 20–25% in SUVmax and Patlak-derived Ki, and 32% in NLR3k-derived Ki are likely to represent treatment effects.
- Yamamoto Y, Nishiyama Y, Ishikawa S, Nakano J, Chang SS, Bandoh S, et al. Correlation of 18F-FLT and 18F-FDG uptake on PET with Ki-67 immunohistochemistry in non-small cell lung cancer. Eur J Nucl Med Mol Imaging 2007;34:1610–6. CrossRef
- Troost EG, Vogel WV, Merkx MA, Slootweg PJ, Marres HA, Peeters WJ, et al. 18F-FLT PET does not discriminate between reactive and metastatic lymph nodes in primary head and neck cancer patients. J Nucl Med 2007;48:726–35. CrossRef
- Kenny LM, Vigushin DM, Al-Nahhas A, Osman S, Luthra SK, Shousha S, et al. Quantification of cellular proliferation in tumor and normal tissues of patients with breast cancer by [18F]fluorothymidine-positron emission tomography imaging: evaluation of analytical methods. Cancer Res 2005;65:10104–12. CrossRef
- Vesselle H, Grierson J, Muzi M, Pugsley JM, Schmidt RA, Rabinowitz P, et al. In vivo validation of 3′deoxy-3′-[(18)F]fluorothymidine ([(18)F]FLT) as a proliferation imaging tracer in humans: correlation of [(18)F]FLT uptake by positron emission tomography with Ki-67 immunohistochemistry and flow cytometry in human lung tumors. Clin Cancer Res 2002;8:3315–23.
- Barthel H, Cleij MC, Collingridge DR, Hutchinson OC, Osman S, He Q, et al. 3′-deoxy-3′-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Cancer Res 2003;63:3791–8.
- Salskov A, Tammisetti VS, Grierson J, Vesselle H. FLT: measuring tumor cell proliferation in vivo with positron emission tomography and 3′-deoxy-3′-[18F]fluorothymidine. Semin Nucl Med 2007;37:429–39. CrossRef
- Dittmann H, Dohmen BM, Paulsen F, Eichhorn K, Eschmann SM, Horger M, et al. [18F]FLT PET for diagnosis and staging of thoracic tumours. Eur J Nucl Med Mol Imaging 2003;30:1407–12. CrossRef
- Yamamoto Y, Nishiyama Y, Kimura N, Ishikawa S, Okuda M, Bandoh S, et al. Comparison of (18)F-FLT PET and (18)F-FDG PET for preoperative staging in non-small cell lung cancer. Eur J Nucl Med Mol Imaging 2008;35:236–45. CrossRef
- Buck AK, Halter G, Schirrmeister H, Kotzerke J, Wurziger I, Glatting G, et al. Imaging proliferation in lung tumors with PET: 18F-FLT versus 18F-FDG. J Nucl Med 2003;44:1426–31.
- Cobben DC, Elsinga PH, Hoekstra HJ, Suurmeijer AJ, Vaalburg W, Maas B, et al. Is 18F-3′-fluoro-3′-deoxy-L-thymidine useful for the staging and restaging of non-small cell lung cancer? J Nucl Med 2004;45:1677–82.
- Shields AF. PET imaging with 18F-FLT and thymidine analogs: promise and pitfalls. J Nucl Med 2003;44:1432–4.
- Buck AK, Kratochwil C, Glatting G, Juweid M, Bommer M, Tepsic D, et al. Early assessment of therapy response in malignant lymphoma with the thymidine analogue [18F]FLT. Eur J Nucl Med Mol Imaging 2007;34:1775–82. CrossRef
- Herrmann K, Wieder HA, Buck AK, Schöffel M, Krause BJ, Fend F, et al. Early response assessment using 3′-deoxy-3′-[18F]fluorothymidine-positron emission tomography in high-grade non-Hodgkin’s lymphoma. Clin Cancer Res 2007;13:3552–8. CrossRef
- Apisarnthanarax S, Alauddin MM, Mourtada F, Ariga H, Raju U, Mawlawi O, et al. Early detection of chemoradioresponse in esophageal carcinoma by 3′-deoxy-3′-3H-fluorothymidine using preclinical tumor models. Clin Cancer Res 2006;12:4590–7. CrossRef
- Kenny L, Coombes RC, Vigushin DM, Al-Nahhas A, Shousha S, Aboagye EO. Imaging early changes in proliferation at 1 week post chemotherapy: a pilot study in breast cancer patients with 3′-deoxy-3′-[18F]fluorothymidine positron emission tomography. Eur J Nucl Med Mol Imaging 2007;34:1339–47. CrossRef
- Chen W, Delaloye S, Silverman DH, Geist C, Czernin J, Sayre J, et al. Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study. J Clin Oncol 2007;25:4714–21. CrossRef
- Kasper B, Egerer G, Gronkowski M, Haufe S, Lehnert T, Eisenhut M, et al. Functional diagnosis of residual lymphomas after radiochemotherapy with positron emission tomography comparing FDG- and FLT-PET. Leuk Lymphoma 2007;48:746–53. CrossRef
- Perumal M, Pillai RG, Barthel H, Leyton J, Latigo JR, Forster M, et al. Redistribution of nucleoside transporters to the cell membrane provides a novel approach for imaging thymidylate synthase inhibition by positron emission tomography. Cancer Res 2006;66:8558–64. CrossRef
- Hoekstra CJ, Hoekstra OS, Lammertsma AA. On the use of the injection catheter for venous blood sampling in quantitative FDG PET studies. Eur J Nucl Med 2000;27:1579. CrossRef
- Boellaard R, van Lingen A, van Balen SCM, Lammertsma AA. Optimization of attenuation correction for positron emission tomography studies of thorax and pelvis using count-based transmission scans. Phys Med Biol 2004;49:N31–8. CrossRef
- Boellaard R, van Lingen A, Lammertsma AA. Experimental and clinical evaluation of iterative reconstruction (OSEM) in dynamic PET: quantitative characteristics and effects on kinetic modeling. J Nucl Med 2001;42:808–17.
- Riddell C, Carson RE, Carrasquillo JA, Libutti SK, Danforth DN, Whatley M, et al. Noise reduction in oncology FDG PET images by iterative reconstruction: a quantitative assessment. J Nucl Med 2001;42:1316–23.
- Boellaard R, van Lingen A, van Balen SC, Hoving BG, Lammertsma AA. Characteristics of a new fully programmable blood sampling device for monitoring blood radioactivity during PET. Eur J Nucl Med 2001;28:81–9. CrossRef
- Hoekstra CJ, Hoekstra OS, Lammertsma AA. On the use of image-derived input functions in oncological fluorine-18 fluorodeoxyglucose positron emission tomography studies. Eur J Nucl Med 1999;26:1489–92. CrossRef
- Boellaard R, Oyen WJ, Hoekstra CJ, Hoekstra OS, Visser EP, Willemsen AT, et al. The Netherlands protocol for standardisation and quantification of FDG whole body PET studies in multi-centre trials. Eur J Nucl Med Mol Imaging 2008; [Epub ahead of print]. doi:10.1007/s00259-008-0954-3
- Erdi YE, Mawlawi O, Larson SM, Imbriaco M, Yeung H, Finn R, et al. Segmentation of lung lesion volume by adaptive positron emission tomography image thresholding. Cancer 1997;80:2505–9. CrossRef
- van der Weerdt AP, Klein LJ, Boellaard R, Visser CA, Visser FC, Lammertsma AA. Image-derived input functions for determination of MRGlu in cardiac (18)F-FDG PET scans. J Nucl Med 2001;42:1622–9.
- Patlak CS, Blasberg RG, Fenstermacher JD. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 1983;3:1–7.
- Akaike H. A new look at the statistical identification. IEEE Trans Automat Contr 1978;19:716–23. CrossRef
- Schwarz G. Estimating the dimension of a model. Ann Statist 1978;6:461–4. CrossRef
- Hoekstra CJ, Paglianiti I, Hoekstra OS, Smit EF, Postmus PE, Teule GJ, et al. Monitoring response to therapy in cancer using [18F]-2-fluoro-2-deoxy-D-glucose and positron emission tomography: an overview of different analytical methods. Eur J Nucl Med 2000;27:731–43. CrossRef
- Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;1:307–10.
- Muzi M, Vesselle H, Grierson JR, Mankoff DA, Schmidt RA, Peterson L, et al. Kinetic analysis of 3′-deoxy-3′-fluorothymidine PET studies: validation studies in patients with lung cancer. J Nucl Med 2005;46:274–82.
- Shields AF, Lawhorn-Crews JM, Briston DA, Douglas KA, Mangner TJ, Muzik O. The reproducibility of FLT PET in patients with untreated non-small cell lung cancer. J Nucl Med 2005;46:426P.
- Smyczek-Gargya B, Fersis N, Dittmann H, Vogel U, Reischl G, Machulla HJ, et al. PET with [18F]fluorothymidine for imaging of primary breast cancer: a pilot study. Eur J Nucl Med Mol Imaging 2004;31:720–4. CrossRef
- Been LB, Elsinga PH, de Vries J, Cobben DC, Jager PL, Hoekstra HJ, et al. Positron emission tomography in patients with breast cancer using (18)F-3′-deoxy-3′-fluoro-l-thymidine ((18)F-FLT) – a pilot study. Eur J Surg Oncol 2006;32:39–43. CrossRef
- Dimitrakopoulou-Strauss A, Strauss LG. The role of 18F-FLT in cancer imaging: does it really reflect proliferation? Eur J Nucl Med Mol Imaging 2008;35:523–6. CrossRef
- Muzi M, Spence AM, O’Sullivan F, Mankoff DA, Wells JM, Grierson JR, et al. Kinetic analysis of 3′-deoxy-3′-18F-fluorothymidine in patients with gliomas. J Nucl Med 2006;47:1612–21.
- Reproducibility of quantitative 18F-3′-deoxy-3′-fluorothymidine measurements using positron emission tomography
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
European Journal of Nuclear Medicine and Molecular Imaging
Volume 36, Issue 3 , pp 389-395
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- Positron emission tomography
- Non-small-cell lung cancer
- Industry Sectors
- Author Affiliations
- 1. Department of Respiratory Medicine, VU University Medical Centre, Amsterdam, The Netherlands
- 4. Department of Radiotherapy, VU University Medical Centre, Amsterdam, The Netherlands
- 2. Department of Nuclear Medicine & PET Research, VU University Medical Centre, PO Box 7057, 1007 MB, Amsterdam, The Netherlands
- 3. Department of Clinical Epidemiology & Biostatistics, VU University Medical Centre, Amsterdam, The Netherlands
- 5. Department of Otolaryngology/Head and Neck Surgery, VU University Medical Centre, Amsterdam, The Netherlands